Studies with mice bearing mammary carcinomas indicate that irradiation following administration of hypoxic cell sensitizers significantly enhances local tumor control. Normal tissue damage appears to be enhanced to an extent less than or equal to the tumor. The proposed project will extend previous single-dose investigations to fractionated radiotherapy and hypoxic cell sensitizers to determine optimal time-dose relationships and to compare the combined modality to effects observed in animals treated with radiation alone. Because kinetics of reoxygenation are known to differ among tumor lines, several tumor lines will be examined to select three or four with differing reoxygenation kinetics. These then will be studied to determine the extent hypoxic cell sensitizers reduce the heterogeneity of response to fractionated irradiation. Tumor response will be evaluated by determining the radiation dose required for local control of tumors in 50% of the animals (TCD50). Normal tissue responses will be studied with emphasis on the acute proliferative responses of stem cells of the gut and skin and the late effects of contraction and fibrosis in skin and connective tissues of the leg.